Paper Citing NAMD - Abstract
Park, S.; Saven, J.G.
Simulation of pH-dependent edge strand rearrangement in human beta-2 microglobulin
PROTEIN SCIENCE, 15:200-207, JAN 2006
Amyloid fibrils formed from unrelated proteins often share morphological similarities, suggesting common biophysical mechanisms for amyloidogenesis. Biochemical studies of human beta-2 microglobulin (beta(2)M) have shown that its transition from a Water-soluble protein to insoluble aggregates can be triggered by low pH. Additionally, biophysical measurements of beta(2)M using NMR have identified residues of the protein that participate in the formation of amyloid fibrils. The crystal structure of monomeric human beta(2)M determined at pH 5.7 shows that one of its edge beta-strands (strand D) adopts a conformation that differs from other structures of the same protein obtained at higher pH. This alternate beta-strand arrangement lacks a beta-bulge, which may facilitate protein aggregation through intermolecular beta-sheet association. To explore whether the pH change may yield the observed confomational difference, molecular dynamics simulations of beta(2)M were performed. The effects of pH were modeled by specifying the protonation states of Asp, Glu, and His, as well as the C terminus of the main chain. The bulged conformation of strand D is preferred at medium pH (pH 5-7), whereas at low pH (pH < 4) the straight conformation is observed. Therefore, low pH may stabilize the straight conformation of edge strand D and thus increase the amyloidogenicity of P2M.
